The rising prevalence of obesity worldwide and its associated metabolic derangements, such as type 2 diabetes mellitus (T2DM), pose an enormous public health challenge (Van Gaal et al. (2006) Nature 444:875-880). Diabetes is a chronic and progressive disease characterized by insulin resistance and insulinopenia resulting from pancreatic beta cell failure and decreases in pancreatic beta cell mass (Ferrannini (2010) Cell Metabol. 11:349-352; Kasuga (2006) J. Clin. Invest. 116:1756-1760; Muoio and Newgard (2008) Nat. Rev. Mol. Cell. Biol. 9:193-205). Despite initial success in glycemic control with oral medications, patients with T2DM typically exhibit worsening glucose homeostasis over the span of a few years (Kahn et al. (2006) New Engl. J. Med. 355:2427-2443; Matthews et at (1998) Diab. Med. 15:297-303; Turner et al. (1996) Annal. Int. Med. 124:136-145). The natural history of T2DM includes a continuous decline in pancreatic beta cell function as illustrated by longitudinal follow up studies of patients (Festa et al. (2006) Diabetes 55:1114-1120). This deterioration leads to the need for additional therapies as well as the cumulative development of diabetic complications.
Increasing adiposity is directly correlated with adipose inflammation and elaboration of proinflammatory cytokines, such as tumor necrosis factor-α, but whether this low-grade chronic inflammation is sufficient to trigger islet dysfunction is unknown (Hotamisligil (2006) Nature 444:860-867; Ouchi et al. (2011) Nat. Rev. Immunol. 11:85-97; Rosen and Spiegelman (2006) Nature 444:847-853; Shoelson et al. (2006) J. Clin. Invest. 116:1793-1801). Other factors, such as amyloidosis, glucolipotoxicity, failure of pancreatic beta cell expansion, apopotosis, and pancreatic beta cell dedifferentiation have also been posited (Kitamura (2013) Nat. Rev. Endocrinol. 9:615-623; Leroith and Accili (2008) Nat. Clin. Pract. Endocrinol. Metabol. 4:164-172; Muoio and Newgard (2008) Nat. Rev. Mol. Cell. Biol. 9:193-205; Prentki and Nolan (2006) J. Clin. Invest. 116:1802-1812; Weir et al. (2009) Diabetes Obes. Metabol. 11:82-90).
Adipsin, also known as complement factor D, was the first adipokine described (Cook et al. (1987) Science 237:402-405). In fact, adipsin is one of the major proteins of adipose cells, but paradoxically circulating adipsin levels decline in many animal models of obesity and diabetes (Flier et al. (1987) Science 237:405-408). Adipsin was later identified to be complement factor D (Rosen et al. (1989) Science 244:1483-1487; White et al. (1992) J. Biol. Chem. 267:9210-9213), which catalyzes the rate-limiting step of the alternative pathway of complement activation (Xu et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98:14577-14582). Since then, adipsin has been shown to play pivotal roles in models of ischemia reperfusion (Stahl et al. (2003) Amer. J. Pathol. 162:449-455) and sepsis (Dahlke et al. (2011) J. Immunol. 186:3066-3075). Functions of this molecule include both the formation of the C5-C9 membrane attack complex and the generation of a number of signaling molecules, including the anaphylatoxins C3a and C5a (Ricklin et al. (2010) Nat. Immunol. 11:785-797). However, the function of adipsin in relation to energy homeostasis and systemic metabolism has been unknown.
The increasing awareness of the interplay between the immune system and adipose tissue biology focuses attention on complement biology in the pathogenesis of T2DM (Shu et al. (2012) Semin. Immunol. 24:436-442). Certain proteins of the complement pathway are preferentially expressed in the adipose tissue and some components, like adipsin, are dysregulated in models of obesity and diabetes (Choy et al. (1992) J. Biol. Chem. 267:12736-12741; Flier et al. (1987) Science 237:405-408; Zhang et al. (2007) Am. J. Physiol. Endocrinol. Metabol. 292, E1433-E440). Receptors for complement-derived peptides are widely expressed on multiple immune cell types (Ricklin et al. (2010) Nat. Immunol. 11:785-797). Studies using mice deficient in C3aR1 or employing an antagonist of the receptor have shown protection against obesity, reductions in adipose tissue inflammation, and improved insulin sensitivity (Lim et al. (2013) FASEB J. 27:822-831; Mamane et al. (2009) Diabetes 58:2006-2017).
Despite the well-known association between obesity, adipose inflammation and malfunction of pancreatic beta cells, the molecular link remains to be established (Lumeng and Saltiel (2011) J. Clin. Invest. 121:2111-2117). Accordingly, there is a great need to identify molecular regulators of pancreatic beta cell disorders, including the generation of diagnostic, prognostic, and therapeutic agents to effectively control such disorders in subjects.